Estrogens regulate many essential physiological processes and are needed for the functional maintenance of many adult target tissues within and outside of the reproductive system. They can, however, have deleterious actions in promoting breast and uterine cancers. This balance of desirable versus undesirable activities in diverse target tissues offers an intriguing opportunity for the development of tissue-selective estrogens that provide a net benefit with minimal risk for menopausal hormone replacement, such as ones affording bone health, relief from vasomotor symptoms, and metabolic and vascular protection without stimulation of the breast or uterus.
It is now recognized that estrogens act through estrogen receptors (ERs) by utilizing two distinct signaling pathways, the direct nuclear-initiated (“genomic”) pathway, wherein ER functions as a chromatin-binding ligand-regulated transcription factor, and the extranuclear-initiated (“non-genomic”) pathway, which involves kinase cascades initiated by ER action from outside the nucleus. The activation of specific kinases by the action of estrogens through extranuclear ER action is generally rapid and often transient, and its initiation likely requires only the input of a triggering signal by the ER-hormone complex to initiate a kinase cascade and cellular activities through the extranuclear-initiated ER signaling pathway. By contrast, the activation of genes through the direct nuclear ER signaling pathway appears to require a more sustained action of ER-hormone complexes, sufficient to effect dissociation of heat shock proteins, recruit coregulator proteins, stimulate ER binding to chromatin, alter chromatin architecture and modify histones, and activate RNA pol II to initiate gene transcription. ER ligands with potent nuclear ER activity form more kinetically stable receptor-cofactor complexes, and coactivator binding can slow ligand dissociation rates by orders of magnitude (Gee, Mol Endocrinol 13, 1912-1923, 1999). Thus, it seemed possible that ER ligands preferential for extranuclear over nuclear ER signaling might be obtained by redesigning the structures of certain estrogens in ways that would preserve their essential chemical features, a phenol and often a secondary alcohol, as well as their overall composition and geometry, but would reduce considerably their high affinity ER binding.
There is great medical need for estrogens having favorable pharmacological profiles, supporting desirable activities for menopausal women such as bone health, relief from vasomotor symptoms, and metabolic and vascular protection but lacking stimulatory activities on the breast and uterus.